Is MITF p.Arg347Cys (c.1039C>T) pathogenic?

MITF p.Arg347Cys (c.1039C>T) is classified Conflicting classifications of pathogenicity in MITF (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-11). AlphaMissense: likely pathogenic (0.999); Very rare (popmax 0.000169%, nfe); Associated with MITF-related disorder.

What condition is associated with MITF p.Arg347Cys (c.1039C>T)?

MITF p.Arg347Cys (c.1039C>T) is associated with MITF-related disorder, Tietz syndrome, Waardenburg syndrome type 2A (ClinVar).

How common is MITF p.Arg347Cys (c.1039C>T) in the general population?

MITF p.Arg347Cys (c.1039C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MITF p.Arg347Cys (c.1039C>T)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

MITF p.Arg347Cys

c.1039C>T · rs1559751245 · VCV1191164

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

MITF-related disorder

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 7% in MITF
REVEL	0.898	moderately pathogenic-leaning
SaProt	LLR -14.71	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 7,490 bp · p 4.1e-07 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,948 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,952 alleles · very rare exomes 2/1,461,710 · genomes 0/152,242 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MITF
Protein: p.Arg347Cys
Coding: c.1039C>T
MANE Select: NM_001354604
dbSNP: rs1559751245
Type: single nucleotide variant
Location: chr3:69959280 (GRCh38)
Gene constraint: LOEUF 0.482 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 62.25 · 12 PDB
Residue 347: the bhlh domain

Full MITF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MITF-related disorder

Also linked: Tietz syndrome Waardenburg syndrome type 2A melanoma, cutaneous malignant, susceptibility to, 8

Similar variants

MITF p.Arg347His Uncertain significance ★★ ⚠ same residue
MITF p.Arg347Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
MITF p.Arg347Leu Uncertain significance ★ ⚠ same residue
MITF c.1031+1G>A Pathogenic ★★ same condition
MITF c.1179+1G>A Pathogenic ★★ same condition
MITF c.355-1062G>C Pathogenic/Likely pathogenic ★★ same condition
MITF c.880+1G>A Likely pathogenic ★★ same condition
MITF c.955+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mitf-p-arg347cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown